Despite the increasing incidence of cardiovascular disease, there are few effective biomaterials currently available for clinical vascular applications. Currently available synthetic biomaterials such as polyethylene terephthalate have a range of vascular applications including endovascular grafting, heart valve replacement, vascular/myocardial patches and vascular closure devices, but perform poorly as vascular surgical conduits.
An increasing number of implantable devices used in cardiovascular repair, including heart valves and endovascular stents, are made using metal alloys (Singh et al., J. Mat. Sci. Mat. Med., 18:725 (2007)). Metallic surfaces are inherently thrombogenic, a property that is currently masked with profound pharmacological platelet suppression. Following deployment of a stent, the low rates (1-2%) of early thrombosis are maintained only with adherence to dual antiplatelet therapy (DART) with aspirin and a thienopyridine (Urban et al., Lancet, 369:619 (2007)). In the era of drug-eluting stents (DES), the appropriate duration of DAPT remains unclear, but it is increasingly recognized to be dependent on the stent platform. The latest clinical data demonstrate that second generation zotarolimus-eluting DES continue to carry an ongoing risk of thrombosis of up to 0.6% per year, increasing dramatically to 3.6% if DAPT is discontinued within the first month. Confounding this issue, DAPT carries an inherent risk of bleeding, significantly increasing if therapy is continued for 12 months or longer (Valgimigli et al, Circulation, 125:2015 (2012)). A stent platform with enhanced hemocompatibility would provide a clear benefit.
The removal of fibrin and the breakdown of blood clots, termed fibrinoloysis, centrally involves plasminogen. A variety of activating factors, including tissue plasminogen activator (tPA), cleave plasminogen to its active form, plasmin (Marder et al., Stroke J. Cereb. Circ., 41:S45 (2010)). Plasmin is a 90 kDa, two-chain proteolytic enzyme, capable of degrading multiple proteins in both the plasma and extracellular space, but in particular fibrin. For materials applications, adaptation of this pathway to generate clot lysing surfaces has generated much interest (Li et al., Colloids Surf. B Biointerfaces, 86:1 (2011)). One approach has been to expose lysine-rich surfaces to plasma, preferentially sequestering plasminogen for further activation. In vitro, this method has shown clot lysis on both polyurethane and cobalt-chromium substrates (Chen et al., J. Biomed. Mater. Res. A., 90:940 (2009); Wang et al., J. Biomater. Sci. Poly., Ed., 24:684 (2013)). Alternatively, direct immobilization of endogenous regulators of thrombus formation, such as thrombomodulin or tPA onto biomaterial surfaces has shown promise, though necessitating a series of chemical intermediates attached to a polyurethane interface for attachment (Qu et al., Adv. Healthcare Mat., 3:30 (201.4); Wu et al., Acta Biomater., 7:1993 (2011)).
This work highlights important challenges in the adaptation of fibrinolytic agents to enhance biomaterial hemocompatibility, including the need for complex linker chemistry schemes for robust attachment and the long-term retention of biologically active substrates. Adaptation to inert metal platforms with varied three-dimensional geometries such as stents further accentuates these difficulties.
It is an object of the present invention to provide materials which are suitable for vascular application that are biocompatible and not thrombogenic having very low thrombogenicity and a method for safely and securely attaching them to medical substrates without altering or decreasing activity.